2-Alkoxybenzoylamino acids

ABSTRACT

WHEREIN R represents an alkyl group having from 5 to 12 carbon atoms and Y represents a methylene or propylene group, possess superior antipyretic and analgic effects. Compounds of this formula are produced by reacting a 2-alkoxybenzoyl halide with an amino acid.   2-Alkoxybenzoylamino acids having the formula

United States Patent [1 1 Katori et a1.

[ Dec. 16, 1975 2-ALKOXYBENZOYLAMINO ACIDS [75] Inventors: Tatsuhiko Katori, Tone; Giichi Sato,

Chiba; Takashi Kihara, Narita; Norio Yumoto, Tomisato; Shigeru Makino, Narashino; Juntaro Harada, Yachiyo, all of Japan [73] Assignee: SS Pharmaceutical Co., Ltd., Tokyo,

' Japan [22] Filed: Feb. 5, 1974 [21] Appl. No.: 439,693

[30] Foreign Application Priority Data 3,651,133 3/1972 Ghelardoni et al 260/519 FOREIGN PATENTS OR APPLICATIONS 670,751 l/l966 Belgium 260/519 36-267 5/1958 Japan 260/519 Primary ExaminerAnton I-I. Sutto Assistant Examiner-L. A. Thaxton Attorney, Agent, or FirmOblon, Fisher, Spivak, McClelland & Maier [57] ABSTRACT 2-Alkoxybenzoylamino acids having the formula C ONH-Y -C OOH wherein R represents an alkyl group having from 5 to 12 carbon atoms and Y represents a methylene or propylene group, possess superior antipyretic and analgic effects. Compounds of this formula are produced by reacting a- .2-alkoxybenzoy1 halide with an amino acid.

'6 Claims, No Drawings Z-ALKOXYBENZOYLAMINO ACIDS BACKGROUND OF THE INVENTION 1. Field of the Invention This invention relates to novel 2-alkoxybenzoylamino acids possessing excellent antipyretic and analgic effects and a process for their preparation.

2. Description of the Prior Art 2-alkoxybenzoylamino acids having the formula:

.CONH -Y -COOH wherein R represents an ethyl or an allyl group and Y represents a methylene or an ethylene group are known and have been reported to possess antipyretic, analgic and antispastic eflects (Japanese Patent Publication No. 267/1961).

However, the antipyretic effect of the known 2- alkoxybenzoylamino acids is relatively low and does not last for a sufficient length of time. A need exists, therefore, for 2-alkoxybenzoylamino acids which have a high antipyretic effect which is sustained for prolong periods.

SUMMARY OF THE INVENTION Accordingly, one object of this invention is to provide 2-alkoxybenzoylamino acids possessing excellent antipyretic and analgic effects.

Another object of this invention is to provide 2- alkoxybenzoylamino acids which exhibit an excellent antispastic effect.

Yet another object of this invention is to provide a process for obtaining 2-alkoxybenzoylamino acids having excellent antipyretic effects.

Briefly, these and other objects of the invention as hereinafter will become apparent are achieved by 2- alkoxybenzoylamino acids represented by the formula:

CONH-Y-COOH wherein R represents an alkyl group having from 5 to 12 carbon atoms and Y represents a methylene or propylene group.

DESCRIPTION OF THE PREFERRED EMBODIMENTS It has been found that the compounds having the general formula (I), wherein R represents an alkyl group of from 5 to 12 carbon atoms and Y represents a 1 (II) CONHCH2COOH 0R2 (III) CONH-CH CH CH COOH wherein R represents an alkyl group having 6 to 12 carbon atoms and R represents an alkyl group having 5 to 10 carbon atoms.

The 2-alkoxybenzoylamino acid represented by the formula (I) can be produced by reacting 2-alkoxybenzoyl halide (IV) with an amino acid (V) as follows:

v +H2N-Y-COOH COX (IV) (V) C ONH -Y-COOH wherein X represents a halogen atom and R and Y represent the same as defined above.

In carrying out the process of the present invention, (V) is dissolved in a suitable solvent such as water or the like and to the resultant solution is added dropwise small portions of (IV).

The reaction is preferably conducted in the presence of an acid-receptor such as caustic alkali, alkali carbonate, organic base or the like.

The antipyretic'and analgic effects of the 2-alkoxybenzoyl amino acid represented by formula (I) of this invention are shown below, in comparison with the known compounds described above.

1. I-Iypothermal effect on mice Samples suspended in physiological saline solutions were given i.p. in a dose of mg./Kg.-body weight to groups of 5 male mice of dd strain weighing 25-40 g. and the degree of hypothermy was measured rectumly. The results are shown in Table 1.

2. Anitpyretic effect on rabbits Groups of three rabbits each were immobilized in a cylindrical rabbit settler for 2 hours prior to the beginning of the experiment. The experiment was commenced after a sufficient decrease in the rectal temperature occured. Pyrexia was caused by injecting Lipopolysaccharide B.E. Coli Ozl28zBl2 (DIFCO LAB) as a pyrogen in a dose of 27/ Kg. into the ear vein to obtain a pyrexial curve. The same animals were examinend after more than one week. Samples were administered orally in a dose of 100 mg./Kg. body weight 15 minutes before the injection of the pyrogen. The results are shown in Table 2.

TABLE 2 Compounds Degree of hypothenny Mean Group Y Group R (C) CH Ethyl -0.4 0.1 0.0 0.1

Allyl 0.3 0.2 0.2 0.23 CH n-Hexyl 0.7 0.45 0.5 0.55 n-Octyl 1.3 1.16 1.5 1.32 n-Decyl 0.73 0.95 0.96 0.88 n-Dodecyl 0.55 0.72 0.65 0.64

TABLE 3 Number of writhing after drug administration Drugs Route Number of writhing Control 16.3:101 (for l0 min.) (0.6% Acetic acid) i.p. 20.2:tl6.3 (for -20 min.)

18.3:137 (for 0-20 min.)

Control 2l.0:t1l.1

=-CH p.o. 1 1.2: 6.9 R=Ethyl 16.1:105 (50mg./Kg.) Control 13.31103 Aspirin 16.0: 9.3 (50mg./Kg.) 14.7: 9.9 Y' CH 11.0: 9.1 R=n-Hexyl p.o 8.7: 6.1

-continued Drugs Route Number of writhing (5O mg./Kg.) 9.8: 7.7 Y=-CH 13.0: 9.3 R=n-Octyl 8.8: 7.3 (SOmg/Kg.) 10.9: 8.6 Y=CH 2.2;- 2.4 R=n-Dodecyl p.o 2.2: 2.2 (50mg./Kg.) 1.1: 2.0 Y=CH CH CH 9.51 6.3 R=n-Hcptyl 13.7: 9.9 (50mg./Kg.) 11.6: 8.6 YCl-l CH CH 13.01131 R=nHexy1 11.3:116 (SOmg/Kg.) [22:12.4

CH CH CH 9.2: 7.2 R=n0ctyl 12.7: 7.3 (50 mgJKg.) 12.7: 7.4

(Note) i.p. lntraperitoneal administration p.o. Oral administration 4. Acute toxicity of all compounds of the present invention LD (per os, mice): more than 1 g./Kg.

These compounds may be used as medicaments in human medicine in the form of pharmaceutical compositions. These compositions contain the specified compounds in admixture with a pharmaceutical acceptable organic or inorganic carrier material suitable for internal or parenteral administration. The carrier material is a substance, which does not react with the desired compounds, for example, water, gelatine, lactose, petroleum jelly, starch, magnesium stearate, talc, vegetable oils, benzyl alcohol, gums, polyalkylene glycols, cholesterol or other known medicament carriers. The pharmaceutical compositions can be made up, for example, as tablets or dragees, in liquid form as solutions, suspension, emulsions, ointments, or suppositories. If desired, they are sterilized and/or allowed to contain auxiliary substances such as preserving, stabilizing, wetting or emulsifying agents. Usually, the pharmaceutical compositions are administered orally in a dose of from 50 300 mg. per body.

Having generally described this invention, a more complete understanding can be obtained by reference to certain specific examples, which are included for purposes of illustration only and are not intended to be limiting unless otherwise specified.

EXAMPLE 1 2-n-heptyloxybenzoylglycinez 4 g. of glycine were dissolved in 50 ml. of water and to the resultant solution 12.3 g. of 2-n-heptyloxybenzoyl chloride were added dropwise with stirring under ice cooling. During the addition the reaction mixture was always kept alkaline by adding a 20% sodium hydroxide solution. After the completion of the reaction, the solution was acidified with hydrochloric acid to deposit a white solid. The white solid was collected by filtration and washed with water. Recrystallization from ethyl acetate-n-hexane afforded 7.1 g. (47.3% of yield) of colorless needles having a melting point of 120122C.

Elemental Analysis: as C H NO (293.37).

C H N Calculated (71): 64.41 9.45 4.69 Found (7:): 64.28 9.35 4.73

EXAMPLES 2 6 Using the starting materials described below under the same reaction conditions as of Example 1, there were obtained the following result: 5

Desired products Starting Yield Melting Physical Elemental analysis materials Compounds g point form Found (g) (72) (C) (Calculated) 2 2-n-hexyloxy- Z-n-hexyloxy- 4.4 132- colorless 64.38 7.20 5.42

benzoyl chloride benzoylglycine (37.4) 133 needles (10.2) C H NO 3 2-n-octyloxy- 2-n-octyloxy- 6.2 129- colorless 66.07 7.99 4.82

benzoyl chloride benzoylglycine (25.3 l 30 crystals (21.5) C H NO (66.43) (8.19) (4.56)

4 2-n-nonyloxy- 2-n-nonyloxy- 6.9 l l 8- colorless 66.98 8. l 9 4.5

benzoyl chloride benzoylglycine (42.7) 120 crystals (13.2) C H NO (67.26) (8.47) (4.36)

5 Z-n-decyloxy- 2-n-decyloxy- 6.5 98- colorless 68.93 8.28 4.34

benzoyl chloride benzoylglycine (44.2) l00 crystals (13) C H NO (68.03) (8.71) (4.18)

6 2-n-dodecyl- 2 ndodecyloxybenl 99- colorless 69.21 9. 1 7 4.00

oxybenzoyl zoylglycine (44.3) 101.5 crystals (69.39) (9. l 5) (3.85) chloride (8.27) C H NO (363.50)

EXAMPLE 7 C H N Calculated 68.03 8.7 l 4.18 Found 67.99 8.65 4.2

2-n-octyloxybenzoyl-y-amino-n-butyric acid:

stirring under ice cooling. During the addition the reac- EXAMPLES 8-12 Using the starting materials described below under the same reaction conditions as of Example 7, there Desired products were obtained the following result:

Elemental analysis Starting Compounds Yield Melting Physical Found materials g point form (Calculated) (7c (g) N 8 2-n-amyloxy- 2-n-amyloxy- 2 .9 71 .0- colorless 65 .40 7.79 4.85

benzoyl chloride benzoyl-yamino (49.8) 71.5 needles (4.5) n-butyric acid (65.51) (7.90) (4.77)

C H NO (293.37) 9 2-nhexyloxy- 2-n-hexyloxy- 9.5 67.5 colorless 66.42 8. l 8 4.59

benzoyl chloride benzoyl-'y-amino- (32 .3) 68.8 crystals (23.0) n-butyric acid (66.43) (8.20) (4.56)

11 u 4 (307.39) 10 2-n-he ptyloxy- Z-n-heptyloxy- 3 .5 68.0- colorless 67.30 8.39 4.41

benzoyl chloride benzoyl-7amino- .5) 69.0 crystals (5.0) n-butyric acid (67.26) (8.47) (4.36)

CIBHZTNOI (321.42) 1 l 2-n-nonyloxy- 2-n-nonyloxy- 2 .7 79.2- colorless 68.55 8.91 4.08

benzoyl chloride benzoyl-'y-amino- (43 .7) 80.0 crystals (5.0) n-butyric acid (68.74) (8.94) (4.01)

an s1 4 (349.47) 12 Z-n-decyloxy- 2-n-decyloxy- 4.7 81 .5- colorless 69.24 9.1 3 3.91

benzoyl chloride benzoyl-y-amino- (56.4) 82.7 crystals (6.8) n-butyric acid (69.39) (9.15) (3.85)

2i aa 4 (363.50)

tion solution was kept alkaline by adding a 20% potassium hydroxide solution. As the reaction proceeded the oily 2-n-octyloxybenzoyl chloride disappeared and the solution became clear. After stirring at room tempera- EXAMPLE l3 (Tablet) Prescription: A tablet (400.8 mg.) containing the following ingredients:

2-n-octyloxybenzoylglycine mg. lactose 159 mg. crystalline cellulose mg. talc 0.4 mg.

g stearate 0.4 mg. TOTAL 400.8 mg.

was made by a conventional method to produce a white tablet having the following properties:

-14 Kg. 8 l2 minutes degree of hardness: degradation time:

EXAMPLE 14(lnjection) Prescription: An ampoule (2 ml.) containing the following ingredients:

2-n-octyloxybenzoylglycine 100 mg. anhydrous sodium carbonate 18 mg.

distilled water for injection suitable amounts TOTAL 2.0 ml.

was prepared. The mixture having the above composition was dissolved to form a clear solution. The solution was then sterilized at 120C. for minutes. The pH of this product is about 7.

EXAMPLE 15 (Suppository) Prescription: A suppository (1,200 mg.) containing the following ingredients:

2-n octyloxybenzoylglycine 100 mg. Witepsol W 35 935 mg. Witepsol E 85 165 mg. TOTAL 1,200 mg.

was prepared by homogenously dispersing 2-n-octyloitybenzoyloxyglycine in a finely divided form in a base by CONH-YCOOH wherein R represents an alkyl group having 5 to 12 carbon atoms, and Y represents a methylene or propylene group.

2. The 2-alkoxybenzoylglycine of claim 1, wherein the R represents an alkyl group having 6 to 12 carbon atoms and Y is methylene.

3. The 2-alkoxybenzoylamino acid of claim 1, wherein R represents an alkyl group having 5 to 10 carbon atoms and Y is propylene.

4. The 2-alkoxybenzoylamino acid of claim 1, which is 2-n-octyloxybenzoylglycine.

5. The 2-al koxybenzoylamino acid of claim 1, which is 2-ndodecyloxybenzoylglycine.

6. The .2-alkoxybenzoylamino acid of claim 1, which is 2n-amyloxybenzoyl-'y-amino-n-butyric acid. 

1. ALKOXYBENZOYLAMINO ACID REPRESENTED BY THE GENERAL FORMULA:
 2. The 2-alkoxybenzoylglycine of claim 1, wherein the R represents an alkyl group having 6 to 12 carbon atoms and Y is methylene.
 3. The 2-alkoxybenzoylamino acid of claim 1, wherein R represents an alkyl group having 5 to 10 carbon atoms and Y is propylene.
 4. The 2-alkoxybenzoylamino acid of claim 1, which is 2-n-octyloxybenzoylglycine.
 5. The 2-alkoxybenzoylamino acid of claim 1, which is 2-n-dodecyloxybenzoylglycine.
 6. The 2-alkoxybenzoylamino acid of claim 1, which is 2-n-amyloxybenzoyl- gamma -amino-n-butyric acid. 